Tetrahydrobenzofuranylphenoxypropylamines

ABSTRACT

Tetrahydrobenzofuranylphenoxypropylamines, their physiologically tolerable acid addition salts and a process for their preparation are described. The compounds are useful as antihypertensive agents.

United States Patent Effland et al.

dilly s r975 TETRAHYDROBENZOFURANYLPHENOXY- PROPYLAMINES lnventors: Richard C. Effland, Somerville;

Marc N. Agnew, Plainsboro, both of NJ.

Assignee: American Hoechst Corporation,

Bridgewater, NJ.

Filed: May 17, 1974 Appl. No.: 471,123

US. Cl. 260/3462 R; 424/285 Int. Cl C07d 5/40 Field of Search 260/3462 R [56] References Cited UNITED STATES PATENTS 3,340,266 9/1967 Howe et al. 260/3462 R Primary Examinerll-lenry R. Jiles Assistant ExaminerBernard Dentz Attorney, Agent, or FirmCurtis, Morris & Safford [57] ABSTRACT 8 Claims, No Drawings TETRAHYDROBENZUWURANYLPHENOXY PRGPYILAIi/llllhllli This invention relates to tetrahydrobenzofuranylphenoxypropylamines and their physiologically tolerable acid addition salts as antihypertensive agents, and to a process for the preparation thereof.

The compounds of the invention conform to the general formula wherein R is hydrogen or a straight or branched chain alkyl of from I to carbon atoms in a suitable solvent such as dimethylformamide at about 25 C. to form the corresponding 2-(p-hydroxyphenacyl)cyclohexanone. Anhydrous hydrogen chloride is bubbled into a solution of the Z-(p-hydroxyphenacyl)cyclohexanone in a solvent such as absolute methanol to give the corresponding 2-(p-hydroxyphenyl)-4,5,6,7-tetrahydrobenzofuran, which is then reacted with epichlorhydrin in a suitable solvent, preferably 2-butanone, with an acid scavenger such as potassium carbonate to yield the corresponding 2-[4-(2,3-epoxypropoxy)phenyl]-4,5,6,7- tetrahydroben'zofuran. Finally, the addition of a primary alkylamine of from lto 5 carbon atoms, cycloalkylamine of from 3 to 7 carbon atoms, aniline or a primary phenalkylamine of from 7 to 10 carbon atoms in the presence or absence of a suitable solvent such as a mixture of dimethylformamide and absolute ethanol yields the compounds of the invention. The reaction time is from a half hour to 17 days.

The utility of the compounds of the invention as antihypertensive agents is demonstrated by their ability to lower blood pressure when tested in the spontaneous hypertensive rat by the indirect tail cuff method described in Methods of Pharmacology, Vol. 1, edited by A. Schwartz, Applcton-Century-Crofts, New York, N.Y., p. 135(1971). For example, at a dose of 100 mg/kg of body weight. l-isopropylamino-3-[p-(4,5,6,7- tetrahydrobenzofuran-Z-yl )-phenoxy]- 2-propanol, and l-t-butylamino-3-[p-4,5,6,7-tetrahydrobenzofuran-2- yl)phenoxy]-2-propan0l, and l-cyclohexylamino-B-[p- 4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxy]-2- propanol exhibit a 73, 32, and mm. of mercury drop in blood pressure, respectively, on the 3rd day.

The compounds of the invention may be administered to a patient by any convenient route such as orally, intramuscularly, intravenously; subcutaneously or intraperitoneally. The preferred'route of administration is oral, for example, with an inert diluent, with an edible carrier, in gelatin capsules or tablets.

For the purpose of oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups and the like. These preparations should contain at least 0.5% of the compound, but may be varied depending upon the particular form and may conveniently be between 7% to about 70% by weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions are such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 2 and 1000 milligrams of active compound.

The tablets, pills, capsules, troches, and the like may also contain the following ingredients: a binder such as gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or both. A syrup may contain, in addition to the active compoundssucrose as a sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions must be pharmaceutically pure and non-toxic in the amounts utilized.

Acids useful for preparing the physiologically tolerable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as oxalic, tartaric, citric, acetic, succinic, maleic and ethane disulfonic acids.

EXAMPLE 1 a. A solution of 43 g. of p-hydroxyphenacyl bromide in dimethylformamide is added slowly to a stirred solution of 30 g. of l-(l-pyrrolidino)-l-cyclohexene in dimethylformamide under nitrogen at 25 C. After 6 /2 hours at ambient temperature, water is added and the mixture is stirred overnight. The mixture is poured in 1.5 l. of water and extracted with chloroform. The chloroform extracts are combined, washed with water and dried. The chloroform is evaporated leaving a waxy solid. The solid is recrystallized from acetonitrite to give 2-(4-hydroxyphenacyl)cyclohexanone as a solid.

b. A small quantity of anhydrous l-lCl is added to a solution of 65.0 g of 2 -(4-hydroxyphenacyl)cyclohexanone in absolute methanol. The mixture is refluxed for 3 hours. The methanol is evaporated to leave a brown solid which is dissolved in ether. The ether solution is washed with water and saturated sodium chloride solution, and dried. The ether is removed to leave a yellow solid which is recrystallized from cyclohexane to give 2-(p-hydroxyphenyl)-4,5,6,7-tetrahydrobenzofuran as a yellow crystalline solid.

hexane to give c. 16.7 g of epichlorhydrin and 24.9 g of potassium carbonate are added to a solution of 8.56 g of 2-(phydroxypheny1)-4,5,6,7-tetrahydrobenzofuran in 2- butanone. The mixture is refluxed overnight. The solution is filtered and the filtrate is concentrated to an offwhite solid. The solid is recrystallized twice from hexane to give 2-[4-(2,3-epoxypropoxy)phenyl]-4,5,6,7- tetrahydrobenzofuran as a colorlesssolid.

d. A mixture of 4.5 g of 2-[4-(2,3- epoxypropoxyphenyl ]-4,5,6,7-tetrahydrobenzofuran, 5.55 g of t-butylamine, 40 ml. of dimethylformamide, and 40 ml. of ethanol is stirred at ambient temperature for days. The mixture is poured into. water and extracted with ether. The ether solution is washed with water, dried and concentrated to an off-white solid. The solid is recrystallized from hexane to give l-tbutylamino-3-[p-(4,5,6,7-tetrahydrobenzofuran-2- yl)phenoxy]-2-propanol as colorless crystals, m.p. 104-l06 C.

Analysis:

Calculated for C l-l NO 73.43% .C; 8.51% H;

Found: 73.63% C; 8.56% H; 3.79% N.

EXAMPLE 2 A mixture of 4.5 g of 2-' 4- 2,3-

epoxypropoxyphenyl)]-4,5,6,7-tetrahydrobenzofuran [Example 1(c)], 7.5 g of cyclohexylamine, 30 ml. of dimethylformamide and 30 ml. of absolute ethanol is stirred for 3 hours at 6570 C. The reaction is cooled to ambient temperature and stirred at this temperature for anadditional 73 hours. The resulting yellow solution is poured into water and extracted with ether. The

ether solution is washed with water, dried and concentrated to an off-white solid which is recrystallized from l-cyclohexylamino-3-[p-( 4,5,6,7-

tetrah ydrobenzofuran-2-y1)phenoxy]-2-propanol as colorless crystals, m.p. l20.5-122.5 C.

Analysis; Calculated for C H NO 74.76% C; 8.46% H;

Found; 74.93% C; 8.37% H; 3.59% N.

EXAMPLE'3 A mixture of 4.5. g of 2-[4-(2,3-

epoxypropoxyphenyl ]-4,5 ,6,7-tetrahyd robenzofuran- [Example1(c)], 7.1 g of aniline, 30 ml. of dimethyl- EXAMPLE 5 A mixture of 2.0 g of 2-[4-(2,3- epoxypropoxypheny1)]-4,5 ,6,7-tetrahydrobenzofuran- [Example 1(c)]; 2.1 g of isopropylamine, 15 ml. of dimethylformamide and ml. of absolute ethanol is I stirred at ambient temperature for five days. The reacformamide and 30 ml.'of absolute ethanol is allowed to 7 stand for 4 days'at 65 C. The reaction mixture is poured into water and extracted with ether. The ether 7 solution is dried and concentrated to a brown oil. Upon standing, the oil solidifies to a brown solid which is purified by dry column chromatography (methylene chloride, silica gel) to give a reddish-brown solid. The solid is' triturated with hot ether to give 1-anilino-3-[p- (4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxyI-2- H propanol as off-white crystals, m.p. 113-115 C.

epoxypropoxyphenyl ]-4 ,5 ,6,7-tetrahydrobenzofuran [Example 1(c)], 2.1 g of phenethylamine, 30 ml. of dimethylformamide and 30 ml. of absolute ethanol is mine tion mixture is poured into water and extracted with ether; the ether solution is washed with water, dried and concentrated to a white solid. The solid is recrystallized from hexane to give 1-isopropylamino-3-[p- (4,5 ,6,7-tetrahydrobenzofuran-2-yl )phenoxy]-2- propanol as fluffy colorless crystals, m.p. 109-1 10 C.

Analysis:

Calculated for C H NO 72.93% C; 8.26% H;

4.25% N. 1 Found: 73.03% C; 8.30% H; 4.33% N.

EXAMPLE 6 a. A stirred solution of 4-t-butyl-l-pyrrolidino-lcyclohexene in dimethylformamide is reacted by the manipulative procedures described in Example 1(a), (b) and (c) to give 5-t-butyl-2-[4-(2,3- epoxypropoxyphenyl)] 4,5,6,7-tetrahydrobenzofuran as a solid.

b. A solution of 8.0 g ,of 5-t-butyl-2-[4-(2,3- epoxyp ropoxyphenyl) ]-4 ,5 ,6,7-tetrahydrobenzofu ran 6.5 g of isopropylamine, 60 ml. of dimethylformamide and 60 ml. of absolute ethanol is allowed to stand at ambient temperature for 17 days. The solvent is removed leaving a red oil which is poured into water and extracted with ether. The ether solution is washed with water, dried and concentrated to a viscous red oil. The oil solidifies to a brown semi-solid upon standing. The semi-solid is recrystallized twice from, acetonitrile to give 1-isopropylamino-3-[p-( 5-t-buty1-4,5 ,6,7- tetrahydrobenzofuran-2-yl)phenoxy]-2-propanol as colorless crystals, m.p. 1 l 11 16C.

Calculated for C H NO 74.77% C; 9.15% H;

Found: 73.71% C; 9.22% H; 3.36 N.

By starting with 4-ethy1-.1-pyrrolidino-1-cyclohexene and. cyclopropylamine, and with 4-isopropyl-1-pyrrolidino-l-cyclohexene and benzylamine instead of 4-tbutyl- 1 -pyrrolidino- 1 -cyclohexene and isopropyla- 1-cyclopropylamino-3-[p-( 5-ethy1-4,5 ,6,7- tetrahydrobenzofuran-Z-yl)phenoxy]-2-propanol and 1-benzylamino -3-[p-(5-isopropy1-4,5,6,7-

tetrahydrobenzofuran-Z-yl)phenoxy1-2-propano1, re-

spectively, are obtained.

EXAMPLE 7 A of 8.0 of 5-t-butyl-2-[4-(2,3-

solution 7 epoxypropoxyphenyl ]4,5,6,7-tetrahydrobenzofuran methylformamide and 60 ml. of absolute ethanol is allowed to stand at ambient temperature for 17 days. The solvent is removed leaving a red oil. The oil is poured into Water and extracted with ether. The ether solution is washed with water, dried, and concentrated to a viscous red oil. The oil solidifies upon standing. The solid is triturated with acetonitrile to give an off-white solid which is recrystallized from acetonitrile to give 1-5- butylamino-3-[p-(5-t-butyl-4,5,6.7-tetrahydrobenzofuran-Z-yl) phenoxyl-Z-propanol as colorless crystals. m.p. ll8-l2l C.

Analysis:

Calculated for C l-l NO 75.15% C; 9.33% 1-1;

3.51% N. Found: 74.63% c, 9.30% a; 3.24% N.

EXAMPLE 8 a. A solution of 4-methyl-l-pyrrolidino-lcyclohexene in dimethylformamide is reacted by the manipulative procedures described above in Example 1(a), (b) and (c) to give an off white solid. The solid is recrystallized twice from acetonitrile to give a very pale yellow crystalline solid of 2-[4-(2,3 epoxypropoxyphenyl)]5-rnethyl-4.5,6,7-tetrahydrobenzofuran.

b. A mixture of 4.0 g of 2-[4-(2,3- epoxypropoxyphenyl)]-5-methyl-4,5,6,7-tetrahydrobenzofuran, 3.84 g of isopropylamine, 40 ml. of dimethylformamide and 40 ml. of absolute ethanol is allowed to stand at ambient temperature for six days. The reaction solution is poured into water and extracted with ether. The ether is washed with water, dried and concentrated to an off-white solid. The solid is triturated with hexane and filtered to give a colorless crystalline solid. Recrystallization from acetonitrile gives l-isopropylamino-3-[p-(5-methyl4,5,6,7- tetrahydrobenzofuran-Z-yl)phenoxyl-2-propanol colorless crystals, m.p. 1 l 11 C.

Analysis:

Calculated for C H NQ 73.43% C; 8.51% H;

4.08% N. Found: 73.77% C; 8.53% H; 3.93% N.

EXAMPLE 9 A mixture of 4.0 g of 2-[4-(2,3- epoxypropoxyphenyl)]- -rnethyl-4.5,6,7-retrahydrobenzofuran, 4.75 g of t-butylamine, 40 ml. of dimethylformamide and 40 ml. of absolute ethanol is allowed to stand at ambient temperature for seven days. The reaction solution is poured into water and extracted with ether. The ether is washed with water, dried and filtered. The ether is evaporated to leave an off-white solid. The solid is triturated with hexane and recrystallized from acetonitrile to give l-t-butylamino- 3[ p-( 5-methyl-4.5 ,6,7-tetrahydrobenzofuran-2- yl)phenoxyl-2-propanol as colorless crystals, ll7.5l 18.5 C.

Analysis:

rn.p.

wherein R is hydrogen or alkyl of from 1 to 5 carbon atoms and R is alkyl of from 1 to 5 carbon atoms. cycloalkyl offrom 37 carbon atoms, phenyl or phenalkyl of from 7-10 carbon atoms; and the physiologically tolerable acid addition salts thereof.

2. A compound defined in claim 1 wherein R is hydrogen or alkyl of l to 4 carbon atoms and R is a member of the group consisting of isopropyl, t-butyl. cyclohexyl. phenyl and phenethyl, and the physiologically tolerable acid addition salts thereof.

3. The compound defined in claim 2, which is lisopropylamino-3-[p-(4,5,6,7-tetrahydrobenzofuran2- yl)phenoxyl-Z-propanol; and the physiologically tolerable acid addition salts thereof.

41. The compound defined in claim 2, which is l-tbutylamino-3-[p-(4,5,6,7-tetrahydrobenzofuran-2- yl)phenoxyl]-2-propanol; and the physiologically tolerable acid addition salts thereof.

5. The compound defined in claim 2., which is lcyclohexylamino-3-[p(4,5.6,7-tetrahydrobenzofuran- 2-yl)phenoxyl-Z-propanol; and the physiologically tolerable acid addition salts thereof.

6. The compound defined in claim 2, which is lisopropylamino-3-[p-(5-t-butyl-4,5,6.7- tetrahydrobenzofuran-2-yl)phenoxyl-2-propanol; and the physiologically tolerable acid addition salts thereof.

7. The compound defined in claim 2, which is l-tbutylamino-3-[p-(5-methyl-4,5,6,7- tetrahydrobenzofuran-2-yl)phenoxy1-2-propanol; and the physiologically tolerable acid addition salts thereof.

8. Process for the preparation of compounds as defined in claim 1 which comprises reacting phydroxyphenacyl bromide with a pyrrolidinocyclohexene in a suitable solvent at about 25 C. to form a 2-(phydroxyphenacyl)cyclohexanone; bubbling anhydrous hydrogen chloride into a solution thereof to form a 2- (p-hydroxyphenyl)-4,5,6,7-tetrahydrobenzofuran; heating said benzofuran with epichlorhydrin in the presence of an acid scavenger in a solvent to give a 2- [4-( 2,3-epoxypropoxyphenyl) ]-4,5,6,7-tetrahydrobenzofuran; and reacting the 2- 4( 2,3- epoxypropoxyphenyl)]-4,5,6,7-tetrahydrobenzofuran with a primary alkylamine of from 1 to 5 carbon atoms, cycloalltylamine of from 5 to 7 carbon atoms, aniline or a phenalkylamine of from 7 to 10 carbon atoms. 

1. A COMPOUND OF THE FORMULA:
 2. A compound defined in claim 1 wherein R1 is hydrogen or alkyl of 1 to 4 carbon atoms and R2 is a member of the group consisting of isopropyl, t-butyl, cyclohexyl, phenyl and phenethyl, and the physiologically tolerable acid addition salts thereof.
 3. The compound defined in claim 2, which is 1-isopropylamino-3-(p-(4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxy)-2 -propanol; and the physiologically tolerable acid addition salts thereof.
 4. The compound defined in claim 2, which is 1-t-butylamino-3-(p-(4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxyl)-2-propanol; and the physiologically tolerable acid addition salts thereof.
 5. The compound defined in claim 2, which is 1-cyclohexylamino-3-(p-(4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxy)-2 -propanol; and the physiologically tolerable acid addition salts thereof.
 6. The compound defined in claim 2, which is 1-isopropylamino-3-(p-(5-t-butyl-4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxy) -2-propanol; and the physiologically tolerable acid addition salts thereof.
 7. The compound defined in claim 2, which is 1-t-butylamino-3-(p-(5-methyl-4,5,6,7-tetrahydrobenzofuran-2-yl)phenoxy) -2-propanol; and the physiologically tolerable acid addition salts thereof.
 8. Process for the preparation of compounds as defined in claim 1 which comprises reacting p-hydroxyphenacyl bromide with a pyrrolidinocyclohexene in a suitable solvent at about 25* C. to form a 2-(p-hydroxyphenacyl)cyclohexanone; bubbling anhydrous hydrogen chloride into a solution thereof to form a 2-(p-hydroxyphenyl)-4,5,6,7-tetrahydrobenzofuran; heating said benzofuran with epichlorhydrin in the presence of an acid scavenger in a solvent to give a 2-(4-(2,3-epoxypropoxyphenyl))-4,5,6,7-tetrahydrobenzofuran; and reacting the 2-(4-(2,3-epoxypropoxyphenyl))-4,5,6,7-tetrahydrobenzofuran with a primary alkylamine of from 1 to 5 carbon atoms, cycloalkylamine of from 5 to 7 carbon atoms, aniline or a phenalkylamine of from 7 to 10 carbon atoms. 